Alkenes intramolecular cyclization

A major initial limitation of the benzocyclobutene approach to o-quinodimethanes was the lack of efficient, large-scale syntheses for many specifically substituted derivatives. Fortunately, recent developments have lemov much of this impediment. Q>nceptually, the synthesis of benzocyclobutenes from aromatic precursors can be envisaged in only a limited number of ways. These include [2 -i- 2] cycloadditions involving benzynes and alkenes, intramolecular cyclization on to a benzyne, cyclizations involving arene anions, and electrocyclic closure of o-quinodimethanes. Benzocyclobutene derivatives can also be prepared by aromatization of bicyclo[4.2.0]octanes. Detailed discussion of variations to these approaches can be found in the cited reviews. The cobalt catalyzed co-oligomerization of 1,5-hexadiynes with al-kynes, especially bis(trimethylsilyl)acetylene, has also been employed for the preparation of specifically substituted benzocyclobutenes. In the latter case the cyclobutenes are often not isolated but converted directly to o-quinodimethanes and subsequent products. ... 

When TMM equivalents are tethered to alkenes, intramolecular cyclization generates bicyclic methylene-cyclopentane derivatives. Cyclization of 394, for example, led to a 51% yield of 395 along with 18% of the uncyclized triene, 396. 35 jhe cyclization reaction proceeded with excellent diastereoselectivity, as shown. Trost has also examined the attachment of chiral auxiliaries to the alkene partner to give asymmetric induction in reactions with TMM equivalents.231... 

The reductive coupling of of dienes containing amine groups in the backbones allows for the production of alkaloid skeletons in relatively few steps [36,46,47]. Epilupinine 80 was formed in 51% yield after oxidation by treatment of the tertiary amine 81 with PhMeSiEh in the presence of catalytic 70 [46]. Notably, none of the trans isomer was observed in the product mixture (Eq. 11). The Cp fuMcTIIF was found to catalyze cyclization of unsubstituted allyl amine 82 to provide 83. This reaction proceeded in shorter time and with increased yield relative to the same reaction with 70 (Eq. 12) [47]. Substitution of either alkene prevented cyclization, possibly due to competitive intramolecular stabilization of the metal by nitrogen preventing coordination of the substituted olefin, and resulted in hydrosilylation of the less substituted olefin. 

Another example of an intramolecular cyclization initiated by reactions of an acyliminium ion [32] with an unactivated alkene has been published by Veenstra and coworkers. In their total synthesis of CGP 49823 (1-116), a potent NK antagonist [33], these authors treated the N,O-acetal 1-112 with 2 equiv. of chlorosulfonic acid in acetonitrile to afford acyliminium ion 1-113 (Scheme 1.29) [34]. This is qualified for a cyclization, creating piperidine cation 1-114, which is then trapped by... 

Diterpenoids related to lambertianic acid were prepared by intramolecular cyclization of either an alkene or an alkyne with a furan ring <2005RJ01145>. On heating amine 101 with allyl bromide, the intermediate ammonium ion 102 was formed which then underwent [4+2] cycloadditions in situ to give the spiroazonium bromides 103 and 104 (Scheme 13). These isomers arose from either endo- or co-transition states. The analogous reaction was also carried out with the same amine 101 and propargyl bromide. The products 105 and 106 contain an additional double bond and were isolated in 58% yield. The product ratios of 103 104 and 105 106 were not presented. 

Intramolecular cyclizations of species containing two alkynes and an alkene group have been reported these take place in an aqueous basic medium and evolve heat as they progress to give isoindolium salts. In the example of 112 cyclizing to give 113, the products were not isolated but were used in subsequent intramolecular cyclizations (Equation 23 and Table 6) <2004KGS177>. 

Several routes to the pyrrolo[l,2-f][l,2,3]triazole skeleton have been described. Intramolecular dipolar cycloaddition of azido-alkenes or alkynes seems to be the most convenient process, although the cyclization efficiency seems to be highly substrate dependent (Scheme 16) <2002JA2134, 2003T1477, 2005SL2187, 2005TL8639>. The formation of this bicyclic system by an intramolecular Heck reaction is an attractive alternative. The recent syntheses of sulfamides by intramolecular cyclization of alkenes or allenes offer a complementary route to the classical... 

Intramolecular arylation of alkenes. The intramolecular palladium-catalyzed condensation of aryl halides with an alkene group (Heck arylation5) can actually proceed more readily than the original bimolecular version. These intramolecular cyclizations typically proceed in acetonitrile at room temperature, particularly when catalyzed by Ag2C03, which also inhibits isomerization of the double bond of the product. They can be used to obtain spiro, bridged, and fused systems. Even tetrasubstituted alkenes can participate, with formation of quaternary centers.6... 

The TV-phosphorylated aziridines (127) are conveniently obtained by intramolecular cyclization of iV-2-chloroethylphosphoramidate anions. The latter can be obtained by addition of AW-dichlorophosphoramidates to alkenes and hydrolytic removal of the chlorine on nitrogen.96... 

Sames et al. have reported the intramolecular cyclization of alkene-amide substrates catalyzed by [Ir(COE)2Cl]2 and the A-heterocyclic carbene ligand, N, A -bis-(2,6-diisopropylphenyl)-imidazolyl, via olefin insertion following oxidative addition of an sp C-H bond (Scheme 11) [117]. 

Intramolecular cyclization of bis(activate alkenes) by reduction at a mercury cathode in aqueous acetonitrile containing tetraethylamraonium toluene-4-sulphonate. Data from ref [120]. 

Radical intermediates are also trapped by intramolecular reaction with an alkene or alkyne bond. At a mercury cathode this process competes with formation of the dialkylmercury [51], At a reticulated vitreous carbon cathode, this intramolecular cyclization of radicals generated by reduction of iodo compounds is an important process. Reduction of l-iododec-5-yne 5 at vitreous carbon gives the cyclopentane... 

Fhe electrochemical generation of alkyl radicals catalysed by square planar nickel complexes has been used to achieve radical-alkene addition reactions. Complex 64 was the catalyst of choice. Intramolecular cyclizations to give five raem-... 

The first example involving a rhodium catalyst in an ene reaction was reported by Schmitz in 1976. An intramolecular cyclization of a diene occurred to give a pyrrole when exposed to rhodium trichloride in isobutanol (Eq. 2) [15]. Subsequently to this work, Grigg utilized Wilkinson s catalyst to effect a similar cycloisomerization reaction (Eq. 3) [16]. Opplozer and Eurstner showed that a n -allyl-rhodium species could be formed from an allyl carbonate or acetate and intercepted intramolecularly by an alkene to afford 1,4-dienes (Eq. 4). Hydridotetrakis(triphenylphosphine)rhodium(l) proved to be the most efficient catalyst for this particular transformation. A direct comparison was made between this catalyst and palladium bis(dibenzylidene) acetone, in which it was determined that rhodium might offer an additional stereochemical perspective. In the latter case, this type of reaction is typically referred to as a metallo-ene reaction [17]. 

Only two examples of the synthesis pyrimidoazocines have been described. In Ref. 82JHC1257, a three-stage synthesis of a new heterocycle system, pyrimido[5,4-c]benz[l]azocine, has been proposed. Condensation of 4-methyl-2-phenyl-5-pyrimidincarboxylate (112) with 3,4-dimethoxy-6-nitrobenzaldehyde (113) led to the substituted alkene 114, which, after catalytic hydrogenation of the nitro group on Raney nickel and subsequent intramolecular cyclization of product 115, was converted into pyrimidobenz[l]azocine 116 (Scheme 32). 

The intramolecular cyclization of oximes with alkene substituents to dihydropyrroles in the presence of radical initiator or by heating was also describedThus, oxime 83 underwent a tandem 1,2-prototropy-cycloaddition sequence and gave an unstable cycloadduct 84, which on treatment with NaOH afforded indolizine 85 (equation 36). ... 

In many of these cases, the nucleophile is a C=C double bond (usually an alkenic group and less frequently an aromatic group). Alkenic oxime mesylates enable intramolecular cyclization by an electrophihc addition of the double bond to the electrophilic intermediate. These reactions are terminated by a proton loss. 

A variety of other reaction conditions have been examined for acylation of alkenes by acyl chlorides. With the use of Lewis acid catalysts, reaction typically occurs to give both enones and jS-halo ketones.7 The latter reaction has been most synthetically useful in intramolecular cyclizations. The following reactions are illustrative. 

Ley and Murray have developed a short synthesis of hirsutine in which the key step involves intramolecular cyclization of a P-oxoester to an alkene with N-phenylselenophthalimide and stannic chloride (Scheme LXVII) ° ... 

Various alkenes react with diphenyl diselenide/(NH4)2S208, in an aqueous acetonitrile as a solvent in the presence of trifluoromethanesulfonic acid to afford the amidoseleny-lation products. It has been observed that some unsaturated nitriles in dioxane undergo intramolecular cyclization reaction to give the corresponding phenylselenolactones. 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

Alkenes are converted to halohydrins by the treatment of halides and water. When halohydrins are treated with a strong base (NaOH), an intramolecular cyclization occurs and epoxides are formed. For example, 1-butene can be converted to butylene oxide via butylene chlorohydrin. 

Use of the allylsilanes as the alkene components in the Heck reaction is illustrated in the regioselective intramolecular cyclization of 120 (equation 98)180. In addition, a high enantioselectivity of 90 %ee is obtained when the chiral phosphine (S)-BINAP is employed. The propargylsilane analog undergoes a similar reaction181. 

Intramolecular cyclizations of alkenylaminyl radicals produced from tetrazenes have been reported. The regioselectivity of cyclizations of aminyl radicals derived from N-3-butenyltetrazene (1), A-4-pentenyl tetrazene (2), and JV-5-hexenyl tetrazene (3) have been studied (78MI1). The position of the alkene moiety is important because other reaction pathways can compete with cyclization. 

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